It is believed that cancer in humans is linked to the activity of non-viral, endogenous oncogenes, and that a substantial portion of these oncogenes code for protein tyrosine kinases. Ligand-mediated receptor tyrosine kinase inhibitors (RTKs), in particular, form a significant subgroup of these oncogenes, and are believed to function as “master switches” for a coordinated cellular communication network that regulates the normal proliferation of eukaryotic cells. Approximately sixty such RTKs have been identified to date; their respective cell signaling pathways having been studied in detail. Moreover, misregulation of RTK signaling pathways has been observed in various types of human cancer, suggesting that signal transduction therapy may be a useful therapeutic modality for the treatment of cancer. Other disease conditions in which RTKs play a pivotal role might also benefit from such therapy. One noteworthy success in this area is imatinib mesylate (available from Novartis Pharmaceuticals Corporation under the tradename GLEEVEC; hereinafter “GLEEVEC”); it is effective in the treatment of Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) by inhibiting translocation of the fusion gene responsible for BCR-ABL tyrosine kinase.
A promising set of targets for therapeutic intervention in the treatment of cancer includes the members of the HER-kinase axis. They are frequently upregulated in solid epithelial tumors of, by way of example, the prostate, lung and breast, and are also upregulated in glioblastoma tumors. Epidermal growth factor receptor (EGFR) is a member of the HER-kinase axis, and has been the target of choice for the development of several different cancer therapies. EGFR tyrosine kinase inhibitors (EGFR-TKIs) are among these therapies, since the reversible phosphorylation of tyrosine residues is required for activation of the EGFR pathway. In other words, EGFR-TKIs block a cell surface receptor responsible for triggering and/or maintaining the cell signaling pathway that induces tumor cell growth and division. Specifically, it is believed that these inhibitors interfere with the EGFR kinase domain, referred to as HER-1. Among the more promising EGFR-TKIs are three series of compounds: quinazolines, pyridopyrimidines and pyrrolopyrimidines.
Two of the more advanced compounds in clinical development include Gefitinib (compound ZD1839 developed by AstraZeneca UK Ltd.; available under the tradename IRESSA; hereinafter “IRESSA”) and Erlotinib (compound OSI-774 developed by Genentech, Inc. and OSI Pharmaceuticals, Inc.; available under the tradename TARCEVA; hereinafter “TARCEVA”); both have generated encouraging clinical results. Conventional prostate cancer treatment with both IRESSA and TARCEVA involves the daily, oral administration of no more than 500 mg of the respective compounds. In May, 2003, IRESSA became the first of these products to reach the United States market, when it was approved for the treatment of advanced non-small cell lung cancer patients.
IRESSA is an orally active quinazoline that functions by directly inhibiting tyrosine kinase phosphorylation on the EGFR molecule. It competes for the adenosine triphosphate (ATP) binding site, leading to suppression of the HER-kinase axis. The exact mechanism of the IRESSA response is not completely understood, however, studies suggest that the presence of EGFR is a necessary prerequisite for its action.
A significant limitation in using these compounds is that recipients thereof may develop a resistance to their therapeutic effects after they initially respond to therapy, or they may not respond to EGFR-TKIs to any measurable degree ab initio. In fact, only 10-15 percent of advanced non-small cell lung cancer patients respond to EGFR kinase inhibitors. Thus, although the compounds may, at first, exhibit strong anti-tumor properties, they may soon become less potent or entirely ineffective in the treatment of cancer. Moreover, since medical research has heretofore not elucidated the biomolecular or pathological mechanism responsible for this resistance, patients who have exhibited such resistance to date have been left with few therapeutic alternatives to treat their disease. For patients that develop resistance, this potentially life-saving therapeutic mechanism did not achieve what they had hoped for and so desperately needed—an active therapy for cancer.
There is a significant need in the art for a satisfactory treatment of cancer, and specifically lung, ovarian, breast, brain, colon and prostate cancers, which incorporates the benefits of TKI therapy, while obviating the resistance developed in response thereto by many patients, and overcoming the non-responsiveness exhibited by still other patients. Such a treatment could have a dramatic impact on the health of individuals, and especially older individuals, among whom cancer is especially common.